Impaired myocellular Ca²⁺ cycling in protein phosphatase PP2A-B56α KO mice is normalized by β-adrenergic stimulation

The activity of protein phosphatase 2A (PP2A) is determined by the expression and localization of the regulatory B-subunits. PP2A-B56α is the dominant isoform of the B'-family in the heart. Its role in regulating the cardiac response to β-adrenergic stimulation is not yet fully understood. We therefore generated mice deficient in B56α to test the functional cardiac effects in response to catecholamine administration versus corresponding WT mice. We found the decrease in basal PP2A activity in hearts of KO mice was accompanied by a counter-regulatory increase in the expression of B' subunits (β and γ) and higher phosphorylation of sarcoplasmic reticulum Ca²⁺ regulatory and myofilament proteins. The higher phosphorylation levels were associated with enhanced intraventricular pressure and relaxation in catheterized KO mice. In contrast, at the cellular level, we detected depressed Ca²⁺ transient and sarcomere shortening parameters in KO mice at basal conditions. Consistently, the peak amplitude of the L-type Ca²⁺ current was reduced and the inactivation kinetics of I_CaL were prolonged in KO cardiomyocytes. However, we show β-adrenergic stimulation resulted in a comparable peak amplitude of Ca²⁺ transients and myocellular contraction between KO and WT cardiomyocytes. Therefore, we propose higher isoprenaline-induced Ca²⁺ spark frequencies might facilitate the normalized Ca²⁺ signaling in KO cardiomyocytes. In addition, the application of isoprenaline was associated with unchanged L-type Ca²⁺ current parameters between both groups. Our data suggest an important influence of PP2A-B56α on the regulation of Ca²⁺ signaling and contractility in response to β-adrenergic stimulation in the myocardium.